Tissue adhesives have many potential medical applications, including topical wound closure, supplementing or replacing sutures or staples in internal surgical procedures, adhesion of synthetic onlays or inlays to the cornea, drug delivery devices, and as anti-adhesion barriers to prevent post-surgical adhesions. Conventional tissue adhesives are generally not suitable for a wide range of adhesive applications. For example, cyanoacrylate-based adhesives have been used for topical wound closure, but the release of toxic degradation products limits their use for internal applications. Fibrin-based adhesives are slow curing, have poor mechanical strength, and pose a risk of infection. Additionally, the Fibrin-based adhesives do not covalently bind to the underlying tissue.
Several types of hydrogel tissue adhesives that have improved adhesive and cohesive properties and are nontoxic have been developed. These hydrogels are generally formed by reacting a component having nucleophilic groups with a component having electrophilic groups to form a covalently crosslinked network. However, these hydrogels are not very effective as surgical adhesives because they typically swell excessively upon the intake of aqueous media, dissolve away at a rate faster than necessary, or lack sufficient adhesion or mechanical strength.
Hydrogels comprising acetoacetate esters crosslinked with amino groups have not been used as tissue adhesives in medical applications. For example, U.S. Pat. No. 4,708,821 describes a process for preparing an aqueous gel which comprises mixing a water-soluble acetoacetylated high molecular compound and a compound containing an amino group in water. Such an aqueous gel is deemed for usage in perfumes and deodorants. The '821 patent does not describe acetoacetylated compound cross-linked with compounds comprising amino groups for medical applications and specifically, for applications related to tissue adhesives.
The main hydrogel bioadhesive polymers known in the art are polyethers or proteins such as albumin. The polyethers are limited in functionality to their end groups, while animal- or human-derived proteins have viral transmission issues. Additionally, the reactive crosslinkable polyether end groups in the art are either photoreactive, requiring the awkward use of a curing lamp, or else they are activated esters that hydrolyze quickly in aqueous solution, or thiols which easily air-oxidize to unreactive disulfides.
Poly(hydroxylic) compounds derivatized with acetoacetate groups and/or polyamino compounds derivatized with acetoacetamide groups by themselves or the combination of these compounds crosslinked with an amino-functional crosslinking compound have not been used for bioadhesive applications.
Applicants' invention addresses the use of an acetoacetylated compound and/or a polyamino compound derivatized with acetoacetamide groups, cross-linked with compounds comprising amino groups for medical applications and specifically for applications related to tissue adhesives. The invention provides a tissue adhesive material with improved characteristics for use in surgical procedures as well as other medical applications. The resulting adhesive has improved adhesion and cohesion to biological substrates (e.g., collagen, muscle tissue), crosslinks readily at body temperature, maintains dimensional stability, does not degrade rapidly, is nontoxic to cells and non-inflammatory to tissue. Additionally, the adhesive has good aqueous and air stability and fast gelation time.
Furthermore, unlike the polyethers in the art, poly(hydroxylic) compounds can be easily converted to the acetoacetate derivative and polyamino compounds can be readily converted to the acetoacetamide derivative at virtually any substitution level, resulting in the ability to tailor reactivity with amino-functional crosslinking compounds and the final hydrogel crosslink density. Unlike the activated ester groups in the polyether art, acetoacetate groups and acetoacetamide groups are stable in water indefinitely. The acetoacetate group is easy to add to many hydroxy-containing organic molecules, rendering a large variety of poly(hydroxylic) compounds useful for amine-crosslinked bioadhesive application. Similarly, the acetoacetamide group is easy to add to many amino-containing organic molecules, rendering a variety of polyamino compounds useful for amine-crosslinked bioadhesive application.